In recent years, lifestyle-related diseases such as obesity and diabetes are brought in question. Accordingly, transcription factors related to expression inductions of adipocyte differentiation marker genes are gaining attention. A peroxisome proliferator-activated receptor (hereinafter, also referred to as “PPAR”) is known to be related to a lot of physiological and/or pathological phenomena such as fat metabolism, regulation of inflammation, cell differentiation, and functional regulation, thereby gaining special attention.
The PPAR is a nuclear receptor belonging to a steroid/retinoid receptor superfamily of ligand responsive transcription factors (Curr. Opin. Chem. Biol., (1997), 1, 235-241; Cell, (1995), 83, 841-850). cDNAs of PPAR are cloned from various animal species and several isoform genes of PPAR are found. Among mammals, three subtypes, PPARα, PPARγ, and PPARδ, are known (J. Steroid Biochem. Molec. Biol., (1994), 51, 157; Gene Expression, (1995), 4, 281; Biochem. Biophys. Res. Commun., (1996), 224, 431; Mol. Endocrinol., (1992), 6, 1634).
The PPARγ is known to be expressed mainly in the adipose tissue, immune organ, adrenal gland, spleen, small intestine, skeletal muscle, and liver. On the other hand, the PPARα is known to be expressed mainly in the liver, heart, kidney, adrenal gland, skeletal muscle, and retina. Also, the PPARδ is known to be universally expressed without tissue specificity. Each of the PPARs forms a stable heterodimer with a retinoid X receptor (RXR), and bind with a specific DNA recognition sequence (PPRE) of the target gene for control.
The PPARγ is induced at a very early phase of an adipocyte differentiation and plays an important role in the adipocyte differentiation as a key regulating (controlling) factor. The first chemical identified as a direct ligand of PPAR was BRL49653, the thiazolidinediones (TZDs) having an antidiabetic effect on type II diabetes. Also, pioglitazone and ciglitazone that are antidiabetic drugs for type II diabetes and are TZD-type (Lehmann, J. M., J. (1995) Biol. Chem. 270, 12953-12956 (non-patent document 1), as well as 15-deoxy-Δ12,14-prostaglandin J2 that is a kind of prostaglandin metabolite (Cell, (1995), 83, 803-812; Cell, (1995), 83, 813-819 (non-patent document 2)) are known as candidates for intrinsic ligands of PPARγ. Moreover, thiazolidinedione derivative that is an insulin sensitizer has been proved to increase the transcription activity of the PPARγ, and known to have an insulin resistance improving effect, hypoglycemic effect, and antihyperlipidemic effect.
Also, since adipocyte hypertrophy, fat accumulation and expression of insulin resistance are suppressed in a PPARγ hetero deficient mouse, a model that the PPARγ mediates adipocyte hypertrophy, fat accumulation and insulin resistance has been proposed (Mol. Cell, (1999), 4, 597 (non-patent document 3)). On the other hand, a thiazolidinedione (TZD) derivative that is a PPARγ agonist is reported to have adipocyte differentiation inductive effect and to increase the number of adipose cells and the weight of adipose tissues (J. Clin. Invest., (1996), 98, 1004-1009 (non-patent document 4)). Therefore, while the TZD derivative is useful as a curative medicine for diabetes, possibility of promoting obesity is a concern. Also, while leptin is known as an antiobesity factor, the expression level of leptin is reported to decrease when the TZD derivative is administered (J. Biol. Chem., (1996), 271, 9455-9459 (non-patent document 5)). Based on these backgrounds, the PPARγ antagonist is expected to control the differentiation of the adipose cell while simultaneously increasing the expression level of leptin, thereby acting as an antiobesity agent.
Compounds that are PPARγ receptor binder having the PPARγ antagonist effect are disclosed by WO01/30343, WO02/060388, WO03/000685, WO2004/024705, and the like. These compounds are supposed to have an antiobesity effect, an adipose tissue weight reducing effect, a hypoglycemic effect, a hypolipidemic effect, and the like.
On the other hand, WO01/26653, WO02/00255, WO02/00256, WO02/00257, and WO02/074342 (patent documents 1-5) disclose the following compound as a carbazole derivative. In these documents, the following compound is disclosed as a phospholipase A2 (sPLA2) inhibitor.

WO02/079154 (patent document 6) discloses the following compound as a sPLA2 inhibitor.

WO98/18464 (patent document 7) discloses the following compound as a sPLA2 inhibitor.

WO96/03377 (patent document 8) discloses the following compound as a muscarine receptor allosteric effector.

WO2004/048333 (patent document 9) discloses the following compound as a PPARγ agonist.
